WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H530342
CAS#: 1187990-87-9
Description: MK-8617 is a potent, selective, orally bioavailabl Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1−3 (HIF PHD1−3) for the Treatment of Anemia (PHD2 IC50 = 1.0 nM; 10-19 hr dog and moneky t1/2). Anemia is a condition of insufficient red blood cells (RBCs) or hemoglobin (Hb) levels that result in reduced functional capability, fatigue, and shortness of breath.
Hodoodo Cat#: H530342
Name: MK-8617
CAS#: 1187990-87-9
Chemical Formula: C24H21N5O4
Exact Mass: 443.16
Molecular Weight: 443.463
Elemental Analysis: C, 65.00; H, 4.77; N, 15.79; O, 14.43
Synonym: MK-8617; MK 8617; MK8617.
IUPAC/Chemical Name: N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide
InChi Key: WXLPERVDMILVIF-UHFFFAOYSA-N
InChi Code: InChI=1S/C24H21N5O4/c1-32-17-9-5-15(6-10-17)21(16-7-11-18(33-2)12-8-16)27-23(30)19-14-25-22(28-24(19)31)20-4-3-13-26-29-20/h3-14,21H,1-2H3,(H,27,30)(H,25,28,31)
SMILES Code: O=C(C1=CN=C(C2=NN=CC=C2)N=C1O)NC(C3=CC=C(OC)C=C3)C4=CC=C(OC)C=C4
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info: Related CAS# 1187992-95-5 (MK-8617 potassium salt) 1187990-87-9 (MK-8617 free)
| Biological target: | MK-8617 is a pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) with an IC50 of 1 nM for PHD2. |
| In vitro activity: | To investigate the exact mechanisms of the fibrogenic effect induced by MK-8617 (MK), a genome-wide gene expression analysis was performed in MK-stimulated HK-2 cells at low (50 nM) and high (1000 nM) doses. KLF5 expression appeared to be markedly up-regulated in high-dose MK-stimulated HK-2 cells (Fig. 5A). After 1000 nM MK administration in vitro, KLF5 mRNA and protein expression were significantly up-regulated (Supplemental Fig. S5E, F). These data indicate that KLF5 might be involved in TIF induction by high-dose MK. To determine the exact mechanisms of KLF5 up-regulation induced by MK, in silico analysis was employed. Computational transcription factor-binding site prediction in the promoter region suggested that HIF-1α may transcriptionally regulate KLF5 (Supplemental Fig. S6). HIF-1α did not bind to the KLF5 promoter under basal conditions and low-dose (50 nM) MK treatment, but HIF-1α binding could be enriched on this promoter by high-dose (1000 nM) MK administration to HK-2 cells (Fig. 5D), demonstrating the direct interaction between HIF-1α and KLF5 in response to high-dose MK. HIF-1α is therefore a strong positive regulator of the KLF5 gene during high-dose MK treatment. Reference: FASEB J. 2019 Nov;33(11):12630-12643. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902673/ |
| In vivo activity: | Whether pharmacological activation of HIF by MK-8617 (MK) improves CKD (chronic kidney disease) associated myopathy was assessed in vivo. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. Reference: Am J Physiol Renal Physiol. 2019 Nov 1;317(5):F1265-F1273. https://journals.physiology.org/doi/full/10.1152/ajprenal.00260.2019?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 5.7 | 12.79 | |
| DMSO:PBS (pH 7.2) (1:3) | 0.3 | 0.56 | |
| DMF | 1.0 | 2.25 |
The following data is based on the product molecular weight 443.46 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Li ZL, Lv LL, Wang B, Tang TT, Feng Y, Cao JY, Jiang LQ, Sun YB, Liu H, Zhang XL, Ma KL, Tang RN, Liu BC. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway. FASEB J. 2019 Nov;33(11):12630-12643. doi: 10.1096/fj.201901087RR. Epub 2019 Aug 26. PMID: 31451021; PMCID: PMC6902673. 2. Qian FY, Li ZL, Guo YD, Gao HC, Gu LH, Le K, Xie CM, Wang B, Zhang ZJ. Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease. Am J Physiol Renal Physiol. 2019 Nov 1;317(5):F1265-F1273. doi: 10.1152/ajprenal.00260.2019. Epub 2019 Oct 7. PMID: 31588798. |
| In vitro protocol: | 1. Li ZL, Lv LL, Wang B, Tang TT, Feng Y, Cao JY, Jiang LQ, Sun YB, Liu H, Zhang XL, Ma KL, Tang RN, Liu BC. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway. FASEB J. 2019 Nov;33(11):12630-12643. doi: 10.1096/fj.201901087RR. Epub 2019 Aug 26. PMID: 31451021; PMCID: PMC6902673. |
| In vivo protocol: | 1. Qian FY, Li ZL, Guo YD, Gao HC, Gu LH, Le K, Xie CM, Wang B, Zhang ZJ. Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease. Am J Physiol Renal Physiol. 2019 Nov 1;317(5):F1265-F1273. doi: 10.1152/ajprenal.00260.2019. Epub 2019 Oct 7. PMID: 31588798. |
Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia
John S. Debenham, Christina Madsen-Duggan, Matthew J. Clements, Thomas F. Walsh, Jeffrey T. Kuethe, Mikhail Reibarkh, Scott P. Salowe, Lisa M. Sonatore, Richard Hajdu, James A. Milligan, Denise M. Visco, Dan Zhou, Russell B. Lingham, Dominique Stickens, Julie A. DeMartino, Xinchun Tong, Michael Wolff, Jianmei Pang, Randy R. Miller, Edward C. Sherer, and Jeffrey J. Hale
Publication Date (Web): November 9, 2016 (Article)
DOI: 10.1021/acs.jmedchem.6b01242
